The topical composition with active compounds from cannabis sativa and calendula officinalis for reduction of skin lesions

ABSTRACT

Disclosed is a topical composition including essential combination of synergistically acting phyto-active materials, non-psychotropic phytocannabinoids from the plant of Cannabis sativa: Cannabidiol, Cannabidiolic acid, Cannabivarin Cannabigerol in combination with extract of Calendula flower and the formulation of the base to ensure the features of anti-inflammation, anti-oxidation, emollient, and bactericidal components. The topical composition is an emollient dedicated for reduction of skin lesions caused by atopic dermatitis, urticaria, radiotherapy and UV induced skin damage and acne. In addition the topical composition could reduce secretion of fats, facilitate deep skin hydration, reduce pores and exert soothing effect.

FIELD OF THE INVENTION

Present invention relates to a topical composition comprisingphytocannabinoids from the plant Cannabis sativa in combination withextract from Calendula officinalis for reduction of skin lesions causedby atopic dermatitis, urticaria, radiotherapy and UV induced skin burndamage, and acne.

BACKGROUND OF THE INVENTION

Inflammation is a biological process during which arachidonic acid isreleased from the phospholipid-based cell membranes and metabolized bycyclooxygenases (COX1 and COX 2) to produce regulatory moleculeseicosanoids: prostaglandins or thromboxanes. The second possibility formetabolism of the arachidonic acid is the pathway controlled bylipoxygenase (LOX) where the enzymatic reaction leads to production ofregulatory molecules belonging to the family of the leukotrienes.Prostaglandins play a key role in the generation of the inflammatoryresponse. Biosynthesis of prostaglandins is significantly increased ininflamed tissue and is contributing to the development of the cardinalsigns of acute inflammation. Certain eicosanoids which are derived fromarachidonic acid are potent mediators of skin inflammation andmodulators of certain T-lymphocyte activities (Samuelsson 1990). Thelevels of the cyclooxygenase product, prostaglandin E2 (PGE2) and thelipoxygenase products, leukotriene B4 (LTB4), 12- and15-hydroxyeicosatetraenoic acid, elevated in biopsy specimens obtainedby keratome from lesional, perilesional, and patients with AD andpsoriasis compared to clinically unaffected patients (Fogh, Herlin andKragballe 1989).

Atopic dermatitis (AD) is a common, clinically defined, chronicinflammatory skin disease frequently associated with allergic rhinitis,asthma and immunoglobulin E (IgE)-mediated food reactions. The highvariability of the clinical phenotype and severity, genetic backgroundand known pathomechanisms strongly suggest a high degree ofpathophysiological heterogeneity. The clinical pattern of eczematousskin lesions is relatively uniform and results from interactivealterations of the skin barrier and the innate and adaptive immunesystems. The pathogenesis of atopic dermatitis involves both epidermalbarrier and immunologic dysfunction. A number of these alterations arecaused by mutations in the genes encoding immune and barrier functionproteins, which may alter the regulation or the structure of the geneproduct itself. Other alterations may be consequences of environmentalfactors such as stress, scratching behaviour, allergen exposure orwashing habits (Thomsen 2014). The epidermal barrier consists of a thinlayer of vital keratinocytes, which slowly differentiate into flatcorneocytes while moving upwards in the epidermis. The thin layer ofdead keratinocytes that make up the stratum corneum covers the vitalparts of the epidermis and protects it against water loss and microbeinvasion. The complex process of epidermal differentiation is disturbedin AD lesions. The corneocytes are attached to one another bycorneodesmosomes which can be degraded by stratum corneum chymotrypticenzyme (SCCE). The decreased activity of SCCE inhibitor lymphoepithelialKazal-type-related inhibitor (LEKTI) in AD skin results in increasedactivity of SCCE thus, the quantity of corneodesmosomes, less cohesionof cells and more shedding of the uppermost corneocytes (Vasilopoulos etal. 2004). The reduction of corneodesmosomes results in thetrans-epidermal water loss and lower hydration of the stratum corneum.The consequences of complete lack of the protease inhibitor LEKTI isdemonstrated by the clinical phenotype of Comel-Netherton syndrome:maximal skin barrier dysfunction and AD-like skin inflammation.Naturally the stratum corneum is slightly acidic due to the naturalmoisturizing factor (NMF), which consists of the filaggrin degradationproducts, lactic acid and urocanic acid (UCA). The optimal pH for SCCEactivity is in the alkaline range, therefore, in case of LEKTIdeficiency for AD patients it is highly recommended to use personalhygiene compositions with slightly acidic or neutral pH (Hovnanian2013). Another reason of epidermal barrier loss is related to activityof profilaggrin gene (FLG), where many genetic studies of FLG haveconfirmed an association between this gene mutation and ichthyosisvulgaris, and clinical AD manifestations. In addition down regulatedproduction of filaggrin at the protein level and infiltrate of T-helpertype 2 (Th2) cytokines contributes to AD development in patients with nofilaggrin mutations (van Smeden and Bouwstra 2016). Small molecules:urea and glycerol improve the skin barrier function. In addition thepetrolatum-comprising stabilizing creams have water-sealing effect andreduce trans-epidermal water loss (Grether-Beck et al. 2012; Fluhr,Darlenski and Surber 2008). The ceramides—another group of waxy lipidmolecules are an essential component to the lipid double layer of thestratum corneum, which content in the stratum corneum correlates withtransepidermal water loss. Therefore, strategy of supplementation ofceramides could be used for treatment of AD (Imokawa et al. 1991).Defects in tight junction formation are a factor which contributes tothe barrier defects in AD. Occludin and tricellulin are transmembranemolecules which form a tight junction functioning as gates for thepassage of water, ions and solutes through the paracellular pathway(Chiba et al. 2008). One of the AD cause reasons can be related withTh2-dominated immune responses and reflected by predominance of the Th2associated cytokines and interleukins IL-4, IL-5, and IL-13. Theapproaches of AD treatment by modulation of immune response are targetedtowards IL-4 receptor alpha chain or the cytokine thymic stromallymphopoietin (TSLP) using specific antibodies. The epidermal dendriticcells which are hyper expressing the high-affinity IgE-receptor FceRIare common in patients with extrinsic AD. Patients with intrinsic ADlack detectable IgEs against common aero- and food allergens. Finally,targeting histamine receptors (HRs) with their antagonists is a widelyused approach to treat AD, as histamine is released in response tovarious skin allergens and, thus, triggers a variety of effects in theskin's immune system (Brandt and Sivaprasad 2011). Infection withStaphylococcus aureus is very common among patients with AD as they havean imbalance in innate and acquired immunity connected to staphylococciand loss of microbiome diversity in the skin. S. aureus may produceexotoxins with superantigenic properties. The cell wall components, suchas lipoteichoic acid and peptidoglycan of S. aureus are recognized byTLRs, especially TLR-2. In response to S. aureus produced extracellular,protein-containing vesicles, the TLR-2 polymorphism-possessing monocytesare producing AD-inflammation inducing IL-6 and IL-12, dermalfibroblasts produce cytokine TSLP (Biedermann et al. 2015; Benenson etal. 2005). The treatment of S. aureus colonisation is usually basedeither on oral or topical antibiotics which might be ineffective due toS. aureus resistance or cause allergies, respectively (Moody, Morrisonand Tyring 2010). Eczema herpeticatum (EH) is clinically defined as thedisseminated infection of eczematous skin disease with the herpessimplex virus (HSV). The pathogenesis of EH is manifested by unmaskingof the HSV entry receptor nectin-1, lack of plasmacytoid dendritic cellsin AD lesions or cathelicidin production in situ, and an abnormal IFN-cresponse to HSV (Blanter et al. 2015). Vitamin D is essential forstimulation of adaptive immunity via toll-like receptors (TLRs), whichincreases production of pro-inflammatory cytokine, enhance of Th2responses and enhances expression of the antimicrobial peptide LL-37 inkeratinocytes. LL-37 deficiency plays a significant role in thepathogenesis of eczema herpeticum (EH). Therefore vitamin D is acting insuppression of inflammatory responses, enhancing antimicrobial peptideactivity and promoting the integrity of the skin barrier permeability,and supplementation, i.e. provides a therapeutic intervention for avariety of skin disorders, including AD (Searing and Leung 2010). Somefindings revealed that impaired homeostasis of oxygen/nitrogen radicalsand increased oxidative stress are involved in the pathophysiology ofchildhood AD, and indicate that suppression of oxidative stress might bea potentially useful strategy for the treatment of AD (Omata et al.2001). The cutaneous inflammation of AD is controlled using topicalcorticosteroids (TCSs) and topical calcineurin inhibitors (TCIs). Thereduction of inflammation is the key for AD control. The symptoms ofvisible lesions on the skin appear as a secondary effect or theconsequence of inflammation. The treatment of AD is based on twoapproaches—reactive treatment which is based on utilisation of topicalcorticosteroids (TCSs) and topical calcineurin inhibitors (TCIs), whichexhibit different mechanisms of action on the skin barrier function andinflammatory cell infiltrate (Kim et al. 2015). The proactive AD therapyis based on application of anti-inflammatory therapy to previouslyaffected skin, together with ongoing, long-term emollient treatment ofunaffected skin. This approach targets invisible inflammation in theusually relapsing ‘problem zones’ of patients with AD (Del Rosso andLevin 2011).

Oxidation and skin inflammation. Many endogenous and environmentalpro-oxidant agents lead to the harmful generation of reactive oxygenspecies (ROS) in the skin. The resulted oxidative stress damagesproteins, lipids, and DNA. An imbalance between ROS and antioxidants canlead to an elevated oxidative stress level. Some evidence indicates thatallergic and inflammatory skin diseases like atopic dermatitis,urticaria and psoriasis are mediated by oxidative stress (Trouba et al.2002). For example, monocytes from patients with atopic dermatitis areprimed to generate ROS in response to zymosan which is a Toll-likereceptor 2 (TLR2) ligand, suggesting that S. aureus may damage diseaselesioned skin by producing ROS. Mast cells generate, mainly,intracellular ROS following the aggregation of FcεRI; these ROS may actas secondary messengers in the induction of several other biologicalresponses (Okayama 2005).

The radiation therapy leads to skin damage which manifests in many formsranging from acute radiodermatitis to chronic skin fibrosis. Acuteradiodermatitis is a generalized erythema that becomes visible within 90days of radiation therapy, often between 2 and 4 weeks presenting as ablanchable sustained erythema. The majority of patients are sufferingfrom complications of secondary radiation therapy. The severity ofradiotherapy induced dermatitis is graded from 1 to 4, where grade 1presents as a faint erythema that may demonstrate dry desquamation,epilation, or decreased sweating. Grade 2 presents as a brighter ortender erythema that demonstrates moist desquamation within skin foldsand also moderate edema. This level of damage typically occurs after 4to 5 weeks from radiotherapy when greater than 40 Gy is given. One totwo weeks following the cessation of radiotherapy, this dermatitisbegins to subside with an increased expression of epidermal growthfactor receptors (McQuestion 2006).

The formation of bullae and the damage to the barrier function of theskin make patients more susceptible to infections, especially by S.aureus. Infection is, however, a rare consequence of radiodermatitis.Grade 3 involves moist desquamation outside of skin folds with pittingedema. Grade 4 is characterized by ulcerated tissue with necrosis orbleeding. When any of these acute reactions fail to resolve, progressionto chronic radiodermatitis or skin fibrosis can occur (Hill et al.2004).

Dermal hydration, which is responsible for the skin's tonicity andturgor, is maintained due to the hydrophila of proteoglycans andglycosaminoglycans such as (GAGs) that are able to retain moisture orprevent Transepidermal Water Loss (TEWL). Proteoglycans have a distinctspatial localization in normal skin and are essential for the correctstructural development, organization, hydration, and functionalproperties of this tissue. The extracellular matrix (ECM) is no longerconsidered to be just an inert supportive material but is a source ofdirective, spatial and temporal, contextual information to the cells viacomponents such as the proteoglycans. The impact of changes inproteoglycans on skin pathology and the wound healing process isrecognized as an important area of pathobiology and is an area ofintense investigation. Recent knowledge on skin proteoglycans can beused to incorporate these molecules into useful adjunct therapies forwound healing and for maintenance of optimal tissue homeostasis in agingskin. In tissues such as the skin, the repair of the dermis afterwounding requires the overlying epithelial layer (keratinocytes), whichtogether orchestrate the cytokine-mediated signalling and paracrineinteractions that are required to regulate the proper extent and timingof the repair process (Smith, Melrose 2015). The importance ofextracellular molecules in the microenvironment, primarily theproteoglycans and glycosaminoglycans in wound healing, cytokinecross-talk between cell types and the role of proteoglycans inregulating these processes has been recently emphasized (Ghatak et al2015).

Pharmacological features of cannabinoids. Centuries ago the extracts ofCannabis sativa plant were used as pain relievers and anti-inflammatoryagents. Currently, the topic of pharmacology features of cannabinoidsbecame a great research focus and it is rapidly growing. The increasingresearch focus on the naturally occurring therapeutic value possessingphyto-compounds such as cannabinoids could be explained by the fact thatmany of the synthetic medical drugs lack therapeutic efficiency or/andmay induce drastic side effects. The C. sativa contains 3 major classesof bioactive molecules: flavonoids, terpenoids and phytocannabinoids.The family of phytocannabinoids compromises approximately 60 types ofterpenophenolic compounds, which are the most important chemicals in theC. sativa plant, possessing highest therapeutic value. Phytocannabinoidsare the only natural analogues of the mammal endocannabinoids.Phytocannabinoids are accumulated in the glandular structures ofcannabis plants, known as trichomes. Depending on the species, cannabiscan accumulate 49-tetrahydrocannabinol (Δ9-THC) which is a majorpsychoactive ingredient and/or cannabidiols (CBD) which arenon-psychoactive ingredients of cannabis plant (Fisar 2009). The mostcommon, therapeutic value possessing, but non-psychoactive cannabinoidsfrom C. sativa are Cannabidiol (CBD), Cannabionic acid (CBDA),Cannabichromene (CBC), Cannabicyclol (CBL), Cannabivarin (CBV),Cannabigerol (CBG), Tetrahydrocannabivarin (THCV), Cannabichromevarin(CBCV), Cannabigerovarin (CBGV), and Cannabigerol Monoethyl Ether (Fisar2009). Family of non-psychoactive phytocannabinoids has a very lowaffinity towards CB1 and CB2—endocannabinoid system related receptors(Pertwee 2008). However, they modulate pharmacological effects byutilizing other endocannabinoid system related receptors, i.e. transientreceptor potential (TRP) channels (Hassan et al. 2014), the peroxisomeproliferators—activated receptor g (PPARg), GPR55, the putativeabnormal-CBD receptor, 5-hydroxytryptamine receptor subtype 1A (5-HT1A),glycine a1 and a1b receptors, the adenosine membrane transporterphospholipase A2, lipoxygenase (LOX) and cyclooxygenase-2 (COX-2)enzymes (Izzo et al. 2009) and Ca²⁺ homeostasis regulation system (Ryanet al. 2009). For example, the phytocannabinoid based anti-inflammatoryaction occurs via inhibition of inflammatory COX-2 protein (Takeda etal. 2008), or inhibition of inactivation of endogenous cannabinoidanandamide, which is an intracellular messenger for regulation of ionchannel activity (van der Stelt and Di Marzo 2005). In addition, CBDdriven modulation of intracellular Ca²⁺ concentration is related to manytherapeutic effects. For example, one of them is anticancer effect viageneration of reactive oxygen species (ROS) for induction of apoptosisin cancer cells (Ramer et al. 2013). Cannabidiol and-Δ-9-tetrahydrocannabinol are neuroprotective antioxidants (Hampson etal. 1998). Within the human body the CB1 and CB2 receptors areinteracting with the endogenous ligands—endocannabinoids, which shouldnot be confused with their analogues—phytocannabinoids. Thephysiological action of endocannabinoids and psychoactivephytocannabinoids is driven via their interactions with the specificclass of Gαi protein-coupled receptors known as a Central CannabinoidReceptor (CB 1) and Peripheral Cannabinoid Receptor (CB2), respectively.The highest abundance of CB1 is located in the central nervous system(basal ganglia, hippocampus, cerebellum and cortex), where they mediatecannabinoid related psychoactive effects. In addition, the CB1 receptorsare present in the nerve-terminals of testis, uterus, vascularendothelium, eye, spleen, ileum, and in adipocytes. In addition, the CB2receptors are distributed within the immune system of the body, in theenriched areas of B lymphocytes (Schwitzer et al. 2015). The moleculesof endocannabinoids are interacting with CB1 and CB2 receptors viamoieties of esters, ethers, long-chain polyunsaturated fatty acids andamides. The function of endocannabinoids is mainly related withregulation of various neurotransmitter release in the peripheral andneural tissues, regulation of fat and energy metabolism and they arealso very important in inflammation processes. Therefore, the componentsof endocannabinoid system—CB1 and CB2 receptors and endogenouscannabinoids—are the targets for the treatment of neurodegenerative(Parkinson's, Alzheimer's and Huntington's) diseases, inflammatory pain,multiple sclerosis, glaucoma, neuropathic pain, obesity and oncologicaldiseases (Maccarrone and Finazzi-Agro 2003).

Psoriasis is an inflammatory disease characterized by epidermalkeratinocyte hyper-proliferation. The most significant mediatorsinvolved in this disorder are those associated with a dominant Th1cytokine profile. D9-THC, CBN and CBD were shown to inhibit keratinocyteproliferation in the low micromolar range and in a cannabinoidreceptor-independent manner. Although the mechanism is incompletelyunderstood, these results support a therapeutic potential ofnon-psychotropic cannabinoids for the treatment of psoriasis (Wilkinsonand Williamson 2007; Nagarkatti et al. 2009).

Calendula officinalis, commonly known as Marigold, is used in theWestern and Asian countries for its anti-inflammatory properties. Themain active components of calendula are sesquiterpene and flavonolglycosides, triterpenoid saponins, triterpene alcohols, flavonoids,carotenoids, xanthophylls, phenolic acids, sterols, mucilage,tocopherols, calendulin, and bitters. According to some reports, theextract of this plant possesses some pharmacological activities whichinclude antioxidant action, anti-inflammatory, antibacterial,antifungal, and antiviral properties. Results of one clinical trialshowed that Calendula officinalis was highly effective in the preventionof acute dermatitis in patients with cancer undergoing postoperativeirradiation (Pommier et al. 2004). It was observed that this plant hascytotoxic effect on tumour cell lines in vitro and anticancer activityin vivo. Some reports showed that mouthwash as gel formulationcomprising calendula extract reduced radiation-induced oropharyngealmucositis (Omata et al. 2001) in patients with head-and-neck cancer(Babaee et al. 2013). There are several examples of topical compositionscomprising cannabidiol in combination with herbal extracts that can bedissolved in lipotropic solvent selected from a group consisting oftriglycerides, hydrocarbons, alcohols, ketones, esters or ethers or theycan be dissolved in the oil from Cannabis sativa seeds or they can bedissolved in hydrophilic solvent selected from the group consisting ofaliphatic polar alcohols or their mixtures with water. DocumentEP2444081B1 2015 April 8 A composition for the treatment of inflammatorydiseases comprising Boswellia serrata extract (15.00 (%, w/w) andCannabis sativa extract 0.55 (%, w/w)) in combination with Petrolatum38.00 (%, w/w), Ethyl oleate 20.00 (%, (w/w)), Isopropyl stearate 15.00(%, w/w), Lanolin hydrogenated 6.00 (%, w/w), Cetyl and stearyl alcohol4.45 (%, (w/w)), Benzyl alcohol 0.80 (%, (w/w)), Dehydroacetic acid 0.20(%, (w/w)). Dedicated for strong and long lasting anti-inflammatory deepreaching effect, e.g. for the treatment of arthritis, muscleinflammations, eczema and psoriasis. The preparation soothes dermatitis,seborrhoea, and acne.

Another document, U.S. Pat. No. 6,949,582B1, describes the Method ofrelieving analgesia and reducing inflammation based on compositioncontaining from about 97.5% to about 99.5% by weight a 70% monohydricalcohol solution, and from about 0.5% to about 2.5% by weight of asynergistic cannabinoid mixture extracted from the female plant Cannabissativa L, including in combination: 9-Tetrahydrocannabinol(delta-9-THC), 9-THC Propyl Analogue (THC-V), Cannabidiol (CBD),Cannabidiol Propyl Analogue (CBD-V), Cannabinol (CBN), Cannabichromene(CBC), Cannabichromene Propyl Analogue (CBC-V), Cannabigerol (CBG),terpenoids, and flavonoids. The liniment is applied topically,preferably by spraying, and the constituents of the mixture are absorbedthrough the skin and interact with cannabinoid receptors in the body andtissues of a human patient to produce therapeutic analgesic andanti-inflammatory effects without undesirable psychotropic side effects.

Document US20120264818A1—Topical Compositions with Cannabis Extractsinvention discloses a method for making a topical composition for thetreatment of pain. The topical composition includes a heat-treatedcannabis material in a carrier. The carrier is typically an aproticsolvent that serves both as an extraction solvent and a skin penetrator.The topical composition may be applied, for example, directly to theskin or through a patch, strip, bandage, or covering.

Suitable preservatives, antioxidants, and chemical stabilizers include,for example, alcohol, benzyl alcohol, butylated hydroxyanisole,butylparaben, calcium acetate, castor oil, chlorocresol,4-chloro-m-cresol, citric acid, disodium edetate, edetate disodium,ethoxylated alcohol, ethyl alcohol, glycerin, methylparaben, parabens,potassium sorbate, propyl gallate, propylene glycol, propylparaben,sodium bisulfite, sodium citrate, sodium metabisulfite, sorbic acid,tannic acid, triglycerides of saturated fatty acids, zinc stearate, andcombinations thereof.

Suitable thickening, stiffening and suspending agents include, forexample, aluminum stearate, beeswax, synthetic beeswax, carbomer 934,carbomer 934P, carbomer 940, cetostearyl alcohol, cetyl alcohol, cetylesters wax, dextrin, glyceryl monostearate, hydroxypropyl cellulose,kaolin, paraffin, petrolatum, polyethylene, propylene glycol stearate,starch, stearyl alcohol, wax, white wax, xanthan gum, bentonite, andcombinations thereof.

In one embodiment, the topical composition is used to treat pain,inflammation, muscle tightness, muscle spasms, skin ulcerations, andscleroderma. In one embodiment, the topical composition is used to treatjoint pain, muscle pain, or arthritis.

The topical compositions, as described herein, may also include one ormore optional ingredients, for example, palliative agents, skinconditioning agents, emollients, humectants, odorants, preservatives,solvents, thickening, stiffening and suspending agents, other agents, ora combination thereof. Other optional agents may be added to thecomposition including, for example, aloe, arachis oil, benzoic acid,cocoa butter, coenzyme Q10, dimethicone, eucalyptus oil, resorcinol,retinol, retinyl palmitate, retinyl acetate, fennel extract, wheyprotein, ceramide, silicone, alpha-hydroxy acids, beta-hydroxy acids,sorbitol, vitamin A, vitamin B, vitamin C, vitamin D, vitamin E.

However, compared to the other compositions herein presented, ourcomposition exhibits very efficient emollient features without usingsynthetic cytotoxic surface active materials, alcohols or polymers. Thecombination of cannabinoids and active compounds of Calendula extractresults in effective anti-inflammatory features that reduce lesionscaused by atopic dermatitis, eczema, urticaria, psoriasis and skindamage caused by UV or/radiation.

SUMMARY OF THE INVENTION

Herein presented invention relates to topical composition comprisingCannabis sativa and Calendula sp. extracts for treatment and/orreduction or/and prevention of lesions resulted from skin inflammation,atopic dermatitis, eczema, urticaria, psoriasis and skin damage causedby UV or/radiation therapy.

The topical composition is based on Cannabis sativa extract in the baseof Water (Aqua), Caprylic/Capric triglyceride, Aloe barbadensis LeafJuice, Olive europaea Fruit Oil, Glycerine, Stearic acid,non-decarboxylated and decarboxylated cannabis resin 3% (to introduce0.5% phytocannabinoids, where ratio of CBDA with CBD corresponds to1:1), Phenoxyethanol, Glyceryl Stearate, Acrylates/C10-30 Alkyl AcrylateCrosspolymer, Tocopherol, Triethanolamine. The topical compositioncomprises essential combination of active materials: phytocannabinoidsfrom plant of Cannabis sativa (Cannabidiol (CBD), Cannabidiolic acid(CBDA), Cannabivarin (CBV) Cannabigerol (CBG)), Calendula sp. flowerextract (0.7%) and olive oil. Dynamic viscosity—2100-2300 mPa, pH—6.Phytocannabinoids and Calendula extract exert anti-inflammatory,anti-oxidative and bactericidal features. The synergetic effect ofphytocannabinoids and other active compounds from Calendula extractresults in deep hydration, reduces skin pores and exerts great soothingeffect. The natural Olive oil moisturises skin, stipulates elasticityand synergistically with phytocannabinoids reduces effects of oxidativeand inflammatory factors which might damage the skin.

DETAILED DESCRIPTION OF THE INVENTION

Materials and Methods

Preparation of Cannabis sativa Extract

Cannabis extract is produced using pulverized, dried (passive dryingprocess for 52 hours at 35-40° C., to reach residual moisture level ofapproximate 10%) biomass of Cannabis sativa “Benico” variety which isderived from the mixture comprising upper plant parts—blossoms andleaves. However, other non-psychotropic Cannabis sativa varieties can beused, where THC concentration rages from 0.0001 to 1%. The CBD and CBDAenriched lipophilic fraction (extract) is produced using an approach ofsupercritical extraction with CO₂ with the following parameters:pressure—465 bar, extraction temperature—70° C., process length—120minutes. The CBD resin is produced by decarboxylation of CBDA resin at160° C. for 5-6 hours.

The amount of major cannabinoids: CBD, CBDA, CBG, CBV, in the cannabisextract is determined according to the ST/NAR/40 “Recommended Methodsfor the Identification and Analysis of Cannabis Products” (UnitedNations, New York, 2009). 10 mg of the resin is homogenised in the 1 mLmixture of methanol and chloroform (v/v, 9:1), for 15 min in theultrasound bath. After centrifugation for 10 min at max g to separateinsolubilities, the prepared samples were analysed using Shimadzu HPLCchromatography system with 30AC automatic injector, CTO-20AC columnthermostat, DGU 20A5 vacuum degas unit, LC-30AD pump and SPD-M20A diodematrix detector. The analysed cannabinoids were fractionated in SupelcoDiscovery HS C18 (25×4.6 mm, 5 μm; RP) with C18 pre-column under theisocratic elution conditions. The temperature of the column—30° C.,mobile phase: acetonitrile 0.1%, flow 0.8 ml/min., separation time 30min.; injection volume—20 μl; detection at the two channels 225 nm and306 nm. The data was analysed with Lab Solutions software. The followinginternal standards were used from Cerilliant: Cannabinol, 1.0 mg/mL(C-046), Cannabidiolic acid (CBDA), 1.0 mg/mL (C-144), Cannabidivarin(CBDV), 1.0 mg/mL (C-140), Cannabigerol (CBG), 1.0 mg/mL (C-141).

Characteristics of Cannabis sativa Extract—

Protein fraction (Kjeldahl Method)—0.63%, Lipids (Soxlet Method) 96.60%,water (Gravimetric Method (103 dgr centigrade))—1.73%. Sum ofCBD/CBDA/CBDV/CBG ˜18%, where the extract comprises 80% of CBDA from thetotal cannabinoids, THC<0.1%.

Preparation of Topical Composition

Vendor and Compound Content % specifications Caprylic/caprictriglyceride 8.76 Aloe barbadensis leaf juice 5.64 Stearic acid 0.94Glycerol monostearate 0.52 Triethanolamine 0.25 Vitamin E 0.4 Water(Distilled) 74.89 Olive europaea (Olive) Fruit Oil 3.33 Glycerol 3.33Acrylates/C10-30 Alkyl Acrylate 0.6 Crosspolymer (Carbopol ® Ultrez 21)Calendula officinalis Flower Extract 0.07 Decarboxylated Cannabis sativa0.25 CBD 15-18% CBD, extract CBD (2.5 mg/mL) 0.75 resin [Satimed] Non-carboxylated Cannabis sativa  0.25 CBDA 15-18% CBDA, extract CBDA (2.5mg/mL) 0.75 resin [Satimed] Phenoxyethanol 0.8

Initially, separately the groups of the following components are mixed:(i) required amounts of Caprylic/capric triglycerides, vitamin E andOlive europaea (Olive) fruit oil, (ii) glycerol, Aloe barbadensis leafjuice and water, (iii) Stearic acid, Glycerol monostearate, (iv)Phenoxyethanol is dissolved in water, (v) Triethanolamine is dissolvedin water (vi) and separately Calendula officinalis flower extract isdissolved in water followed by 2 time filtration through the filter(0.45-0.75 μm). Finally the required amount of Carbopol® Ultrez 21 isdissolved in the largest amounts of water and incubated with mixing forrehydration and soaking. The groups of components (i), (ii) and (iii)are added to reactor and incubated under the slow mixing at 65±2° C.After the temperature is equilibrated Phenoxyethanol solution is added.The homogenisation at 3000 rpm is performed for 3 minutes. Afterhomogenisation the triethanolamine solution is added and homogenisationat 4000 rpm is repeated for 4-5 minutes. The analogical homogenisationcycles are repeated after introduction of Calendula officinalis FlowerExtract solution and decarboxylated and non-decarboxylated extracts ofCannabis sativa. The homogenisation is finalized at 5000 rpm for 10minutes at 65° C. Finally the Carbopol® Ultrez 21 solution and requiredamount of residual water is added. The temperature is adjusted to 70° C.and homogenisation continued at 2000 rpm for 10 minutes. The dynamicviscosity of the product was monitored using Rotational Viscometer(Fungilab, SMART Series H) and pH using Consort (C832) pH-meter. Thecomposition is packaged into vials by maintaining the reactortemperature of 65° C. and slow stirring—60 rpm.

EXAMPLES Example 1

Experimental Procedures

Cell Culturing.

Primary cell line of Human keratinocytes Heka (Gibco,ThermofisherScientic) was cultivated in GIBCO EpiLife serum-free cellculture medium with S7 supplement (ThermofisherScientic) in a microwellplate of 24 vials, 20,000 cells/per well, at 37° C., 5% CO₂. The viablecells after adhesion to the well surface were subjected to 2 μl ofCannabis sativa extract which is used in described topical composition.The extract was prepared after several dissolving steps in ethanol toreach dilution levels from 10² to 10⁷. The blank control—raw Cannabissativa seed oil was prepared analogically. The Cannabis sativa extractcomprises 18% of cannabinoids CBD/CBDA/CBDV/CBG, and 80% of CBDA fromthe total cannabinoid level.

Cell Viability.

Living cells were determined using the CCK-8 kit (Cell Counting Kit,Dojingo) while following the manufacturer's instructions. The amount offormazan resulted by activity of dehydrogenases dye was measured in thediluted media spectrophotometrically at 450 nm.

Quantification of sGAG and GAG.

The evaluation of production of extracellular, membrane andintracellular glycosaminoglycans was performed using Blyscan ELISA kitsfor quantification of sulfonated and non-sulfonated glycosaminoglycansand hyaluronic acid using The Purple-Jelley Hyaluronan Assay (Biocolor,Life Science Assays) after 24 and 48 hours, respectively. For membraneand intracellular analysis of sGAG and GAG, normalized amounts cellswere harvested and fractionated. Assays were carried out by followinginstructions of manufacturer using 50 and 100 μl of harvestedsupernatant.

Results:

Cannabis sativa extract from the topical composition stimulates skinhydration via stimulation of synthesis of glycosaminoglycans andproliferation of human epidermal keratinocytes in vitro.

Transepidermal water loss occurs due to water mobility and ability tomove to the skin surface where it evaporates when exposed to air. sGAGproduction by keratinocytes maintain its content in the skin, whichensures accumulation of water and prevent dryness.

In FIG. 1, plot of absorption units reflect the response of humankeratinocyte's cell viability to the exposure of diluted Cannabis sativaactive materials after 24, 48 and 72 hours of incubation under celloptimal culturing conditions. Sample C—cell viability without exposureto any additives.

Experimental data shows that active materials of Cannabis sativastimulate viability of human keratinocytes. The highest effect wasobserved after 24 h of cell treatment with cannabinoid entourage.

In FIG. 2, the plot shows estimated GAG and sGAG produced in response tothe keratinocyte exposure to diluted active materials after 24 hours ofincubation under cell optimal culturing conditions. Control correspondsto non-treated human keratinocyte culture.

Experimental data shows that active materials of Cannabis sativastimulate production of sGAG and GAG by human keratinocytes. The highesteffect was observed after 24 h of cell treatment with the highestdilution cannabinoid entourage compared to non-treated culture. Thisindicates that keratinocytes exposed to the cannabinoidsCBD/CBDA/CBDV/CBG increase production of GAG and sGAG molecules whichare very important in protection of skin moisture balance.

Example 2

Experimental Procedures

The effects of two phytocannabinoid preparations (JSC SATIMED):“Preparation 1” (in which the concentration of phytocannabinoids is 40mg/ml, extract diluted 4.5 fold with raw Cannabis sativa seed oil) and“Preparation 2” (10 mg/ml of phytocannabinoids, extract diluted 10 foldwith raw Cannabis sativa seed oil), were analysed on the model of acuteinflammation (paw edema) in mice. Three single doses of preparation“Preparation 1” (0.33 mg/kg, 1 mg/kg and 10 mg/kg phytocannabinoids) andone dose of “Preparation 2” (0.23 mg phytocannabinoids) were tested. Theexperiment was performed on 48 mice (BALB/c strain ♀, 6-7 weeks old,average weight 23 g), which were divided into 6 groups (6 mice pergroup), and in all of them paw edema was induced:

1 group. Edema/control—no treatment

2 group. 50 mg/kg prednisolone/control i.p.

3 group. 0.33 mg/kg phytocannabinoids “Preparation 1” p.o.

4 group. 1 mg/kg phytocannabinoids “Preparation 1” p.o.

5 group. 10 mg/kg phytocannabinoids “Preparation 1” p.o.

6 group. 0.23 mg phytocannabinoids “Preparation 2” (topical application)(i.p.—intraperitoneally, p.o.—orally)

Prior to the study, the thickness of the right hind foot of each mousewas measured by a digital micrometre (Mitutoyo, Japan). Acuteinflammation (paw edema) was induced to all mice by an injection of 20μl of 1% λ—carrageenan into their right paw. The effects ofphytocannabinoids on acute inflammation (paw edema) were measured byanalysing the differences between the thickness of the affected andunaffected paw. The test and control materials were administered toanimals one hour after carrageenan injection. Digital micrometremeasurements were carried out after 4, 6 and 24 hours of carrageenaninjection.

Results:

Cannabis sativa extract of topical composition reduces inflammation ofPaw edema in mice model after oral administration and topical treatment.

Paw edema was reduced by all analysed doses of “Preparation 1”. The mosteffective inhibition was observed at 1 mg/kg phytocannabinoid dose,which reduced the rates of paw edema (in comparison to the controlgroup) by 43.2%-57.5% depicted in FIG. 3.

Local application of preparation “Preparation 2” statisticallysignificantly reduced paw edema (up to 44.4%) as shown in FIG. 4.

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1. A topical composition comprising of about 8.76% Caprylic/caprictriglyceride, 5.64% Aloe barbadensis leaf juice, 0.94% Stearic acid,0.52% Glycerol monostearate, 0.25% Trietanolamine, 0.4% Vitamin E,74.89% Water (Distilled), 3.33% Olive europaea (Olive) Fruit Oil, 3.33%Glycerol, 0.6% Acrylates/C10-30 alkyl acrylate crosspolymer, 0.07%Calendula Officinalis Flower Extract, 0.8% Phenoxyethanol, wherein itcomprises 0.75-1% decarboxylated Cannabis sativa extract (0.25% of CBD)and 0.75-1% non-carboxylated Cannabis sativa extract (0.25% CBDA), whereCannabis sativa extract comprises ˜80% of CBDA from the totalcannabinoids, and THC is less than 0.1%.
 2. A topical compositionaccording to claim 1, wherein Cannabis sativa extract is made from anynon-psychotropic Cannabis sativa variety.
 3. A method for producing atopical composition for relieving skin discomfort comprising steps: a)extraction of Cannabis sativa extract, in amount of CBDA 80% from totalcannabinoids, using an approach of supercritical extraction with CO₂with the following parameters: pressure—465 bar, extractiontemperature—70° C., process length—120 minutes. b) decarboxylation ofCannabis sativa extract to produce CBD resin, at 160° C. for 6 hours c)mixing of an emollient non-Newtonian fluid composition comprising about8.76% Caprylic/capric triglyceride, 5.64% Aloe barbadensis leaf juice,0.94% Stearic acid, 0.52% Glycerol monostearate, 0.25% Trietanolamine,0.4% Vitamin E, 74.89% Water (Distilled), 3.33% Olive europaea (Olive)Fruit Oil, 3.33% Glycerol, 0.6% Acrylates/C10-30 alkyl acrylatecrosspolymer, 0.07% Calendula Officinalis Flower Extract, 0.8%Phenoxyethanol with 0.75-1% decarboxylated Cannabis sativa extract(0.25% of CBD) and 0.75-1% non-carboxylated Cannabis sativa extract(0.25% CBDA).
 4. A topical composition according to claim 1, wherein thedynamic viscosity is from 2100 to 2300 mPa and the pH is ˜6.
 5. A methodfor treatment of skin discomfort caused by skin inflammation, atopicdermatitis, psoriasis, urticaria, radiotherapy induced atopicdermatitis, UV and/or oxidation skin and/or thirst or second degree burnand damage associated with skin moisture disbalance, the methodcomprising applying an effective amount of the topical compositionaccording to claim
 1. 6. A method of treatment comprising applying aneffective amount of the composition according to claim 1, forapplication on the entire body of the patient, without the exception ofthe facial area.
 7. A method of proactive AD therapy for long-termemollient treatment of unaffected skin, comprising applying an effectiveamount of the composition of claim 1, wherein the topical composition isapplied on the entire body of the patient, without the exception of thefacial area.
 8. A method of proactive AD therapy after UV, oxidativedamage and third and second degree burns, comprising applying aneffective amount of the composition of claim 1, wherein the topicalcomposition is applied on the entire body of the patient, without theexception of the facial area.
 9. The topical composition according toclaim 2, wherein Cannabis sativa extract is made from “Benico” variety.10. A method for treatment of skin discomfort caused by skininflammation, atopic dermatitis, psoriasis, urticaria, radiotherapyinduced atopic dermatitis, UV and/or oxidation skin and/or thirst orsecond degree burn and damage associated with skin moisture disbalance,the method comprising applying an effective amount of the topicalcomposition according to claim
 2. 11. A method of proactive AD therapyfor long-term emollient treatment of unaffected skin, comprisingapplying an effective amount of the composition of claim 2, wherein thetopical composition is applied on the entire body of the patient,without the exception of the facial area.
 12. A method of proactive ADtherapy after UV, oxidative damage and third and second degree burns,comprising applying an effective amount of the composition of claim 2,wherein the topical composition is applied on the entire body of thepatient, without the exception of the facial area.
 13. A method oftreatment comprising applying an effective amount of the compositionaccording to claim 2, for application on the entire body of the patient,without the exception of the facial area.
 14. A method for treatment ofskin discomfort caused by skin inflammation, atopic dermatitis,psoriasis, urticaria, radiotherapy induced atopic dermatitis, UV and/oroxidation skin and/or thirst or second degree burn and damage associatedwith skin moisture disbalance, the method comprising applying aneffective amount of the topical composition according to claim
 9. 15. Amethod of proactive AD therapy for long-term emollient treatment ofunaffected skin, comprising applying an effective amount of thecomposition of claim 9, wherein the topical composition is applied onthe entire body of the patient, without the exception of the facialarea.
 16. A method of proactive AD therapy after UV, oxidative damageand third and second degree burns, comprising applying an effectiveamount of the composition of claim 9, wherein the topical composition isapplied on the entire body of the patient, without the exception of thefacial area.
 17. A method of treatment comprising applying an effectiveamount of the composition according to claim 9, for application on theentire body of the patient, without the exception of the facial area.